ACAT1/SOAT1 as a Therapeutic Target for Alzheimer's Disease

Shibuya, Yohei; Chang, Catherine C.Y.; Chang, Ta−Yuan

doi:10.4155/fmc.15.161

Cited by 86 publications

(70 citation statements)

References 137 publications

(162 reference statements)

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“…Our study is supported by the previously reported role of ACAT in modulating the intracellular cholesterol pool in various cell types: In macrophages (44) and in bone metastasisderived PC-3 cells (15), ACAT inhibition resulted in increased intracellular FC levels and decreased intracellular CE levels. In neurons, however, blocking ACAT1 activity suppressed CE synthesis without changing intracellular FC levels (16). Locally, CE is formed on the ER membrane where it modulates the function of ER resident ACATs and SREBP1 (38).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, ACAT2-deficient mice are protected against diet-induced hypercholesterolemia due to a loss of cholesterol esterification activity in the intestine and liver (14). In addition, ACATs appear to play a key role in various diseases, such as cancer (15) and Alzheimer's disease (16,17). Despite this significant physiological importance of ACATs, their role in lipid metabolism in adipose tissue is still poorly understood.…”

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confidence: 99%

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In vitro exploration of ACAT contributions to lipid droplet formation during adipogenesis

Zhu

Chen

et al. 2018

Journal of Lipid Research

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As adipose tissue is the major cholesterol storage organ and most of the intracellular cholesterol is distributed to lipid droplets (LDs), cholesterol homeostasis may have a role in the regulation of adipocyte size and function. ACATs catalyze the formation of cholesteryl ester (CE) from free cholesterol to modulate the cholesterol balance. Despite the well-documented role of ACATs in hypercholesterolemia, their role in LD development during adipogenesis remains elusive. Here, we identify ACATs as regulators of de novo lipogenesis and LD formation in murine 3T3-L1 adipocytes. Pharmacological inhibition of ACAT activity suppressed intracellular cholesterol and CE levels, and reduced expression of genes involved in cholesterol uptake and efflux. ACAT inhibition resulted in decreased de novo lipogenesis, as demonstrated by reduced maturation of SREBP1 and SREBP1-downstream lipogenic gene expression. Consistent with this observation, knockdown of either isoform reduced total adipocyte lipid content by approximately 40%. These results demonstrate that ACATs are required for storage ability of lipids and cholesterol in adipocytes.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

In vitro exploration of ACAT contributions to lipid droplet formation during adipogenesis

Zhu

Chen

et al. 2018

Journal of Lipid Research

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“…The massive accumulation of cholesteryl ester is observed in forebrain regions from mouse models or in patients with Alzheimer’s disease (AD) [37, 38], implying that SOAT1 is actively involved in amyloid-β synthesis and AD formation. SOAT1 is one of the targets that may have beneficial effects on AD when blocked [39], and we speculate miR-429-3p may have potential relationships associated with AD.…”

Section: Discussionmentioning

confidence: 99%

Sterol-O acyltransferase 1 is inhibited by gga-miR-181a-5p and gga-miR-429-3p through the TGFβ pathway in endodermal epithelial cells of Japanese quail

Lin

Mersmann

et al. 2019

Preprint

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20Nutrients are utilized and re-constructed by endodermal epithelial cells (EECs) in yolk 21 sac membranes in avian species. Sterol-O acyltransferase 1 (SOAT1) is the key enzyme to 22 convert cholesterol to cholesteryl ester for delivery to growing embryos. During 23 development, absorption of yolk is matched with significant changes of SOAT1 mRNA 24 and enzyme activity. miRNAs regulate angiogenesis and metabolism during mammalian 25 development. However, the involvement of miRNAs in lipid utilization during avian 26 embryogenesis remains ambiguous. 27 Using a miRNA sequencing technique, we found several candidate miRNAs and 28 confirmed expression patterns with real time PCR. They were selected for as candidates 29 targeting the receptor (TGFβ receptor type 1, TGFBR1) that may regulate SOAT1. Similar 30 to SOAT1 mRNA accumulation, the gga-miR-181a-5p expression was gradually elevated 31 during development, but the concentration of gga-miR-429-3p was in the opposite 32 direction. Transfection with gga-miR-181a-5p or gga-miR-429-3p inhibited TGFBR1 and 33 SOAT1 in EECs. The 3' untranslated region (3'UTR) of TGFBR1 was then confirmed to 34 be one of the targets of gga-miR-181a-5p and gga-miR-429-3p. Taken together, expression 35 of miRNAs during embryonic development regulates SOAT1 expression by inhibiting the 36 3'UTR of TGFBR1. This is indicative of possible regulation of avian yolk lipid utilization 3 37 and modification of hatchability by changing miRNA expressions. 38 39 Introduction 40 SOAT1 (sterol-O acyltransferase 1), also named ACAT1 (acyl-Coenzyme A: 41 cholesterol acyltransferase 1), is the key enzyme to catalyze cholesterol conversion into 42 cholesteryl ester, by adding fatty acyl coenzyme A; thus, a less polar molecule is produced 43 [1]. Yolk sac membrane (YSM), a three-layer extraembryonic tissue, serves crucial roles 44 for avian embryos during the entirety of embryonic development. We demonstrated that 45 SOAT1 activity in endodermal epithelial cells (EECs, the third layer of YSM) was 46 activated by specific nutrients and hormones through the cAMP-dependent PKA signaling 47 pathway, and accumulated more cholesterol ester in EECs [2]. 48 The diversity of bio-functions and involvement of non-coding RNAs has raised 49 considerable issues. Non-coding RNAs include short (microRNAs, miRNAs) and long 50 non-coding (lncRNAs), ribosomal (rRNAs), transfer (tRNAs), small nuclear (snRNAs), 51 small nucleolar (snoRNAs), transfer-messenger (tmRNAs) and telomerase RNAs [3]. The 52 functions and regulations of miRNAs have been examined in mammalian species for 53 decades. Mainly, mature miRNAs are paired to 3' untranslated regions (UTR) or 5'UTR 54 by identifying seed regions of target genes [4]. 4 55 During avian embryonic development, the comprehensive whole mount in situ 56 hybridization expression analysis of 111 mature miRNA sequences in chicken embryos 57 revealed that miRNAs showed a variety of patterns in the early stages of development [5]. 58 Tissue specific-expressed miRNAs were also found to regul...

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“…In addition to cholesterol, SOAT can use multiple sterols as substrates and activators 3 . Because of its functional importance, SOAT1 is a potential drug target for Alzheimer’s disease 6 , atherosclerosis 7 and several types of cancers 8–11 .…”

Section: Mainmentioning

confidence: 99%

Inhibition mechanism of human sterol O-acyltransferase 1 by competitive inhibitor

Guan

Niu

Chen

et al. 2020

Preprint

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24Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-25 transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) 26 family 1 . It catalyzes the esterification of cholesterol to generate cholesteryl esters for cholesterol 27 storage 2 . SOAT1 is a target to treat several human diseases 3 . However, its structure and 28 mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 29 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The 30 structure of hSOAT1 dimer at 3.5 Å resolution reveals that the small molecule inhibitor CI-976 31 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, 32 N421 and W420. Our results pave the way for future mechanistic study and rational drug design 33 of SOAT1 and other mammalian MBOAT family members. 34 35 36 37 38 39 40 41 42 43 44 45 46 Main 47Cholesterol is an essential lipid molecule in the cell membranes of all vertebrate. It is important 48 for maintaining the fluidity and integrity of the membrane and is the precursor for the 49 biosynthesis of other crucial endogenous molecules, such as steroid hormones and bile acids. In 50 addition, cholesterol can modulate the activity of many membrane proteins such as GPCR 4 and 51 ion channels 5 . The concentration of cellular free cholesterol is highly regulated 2 . Excessive 52 intracellular cholesterol may form cholesteryl esters, which are catalyzed by the enzyme, sterol 53 O-acyltransferase (SOAT), also called acyl-coenzyme A: cholesterol acyltransferase (ACAT). 54 SOAT catalyzes the reaction between long chain fatty acyl-CoA and intracellular cholesterol to 55 form the more hydrophobic cholesteryl ester, which is then stored in lipid droplets within the cell 56 or transported in secreted lipoprotein particles to other tissues that need cholesterol. In addition 57 to cholesterol, SOAT can use multiple sterols as substrates and activators 3 . Because of its 58 functional importance, SOAT1 is a potential drug target for Alzheimer's disease 6 , 59 atherosclerosis 7 and several types of cancers 8-11 . 60 Previous studies have shown that SOAT1 is an ER-localized multi-transmembrane protein that is 61 evolutionary conserved from yeast to humans 12 . There are two SOAT enzymes in mammals: 62 SOAT1 and SOAT2, which have a protein sequence identity of 48% in human (258 out of 537 63 residues aligned). SOAT1 is ubiquitously expressed in many types of cells 13 ; while SOAT2 is 64 mainly expressed in the small intestine and liver 14 . Due to the pathophysiological importane of 65 SOAT, many SOAT inhibitors of various strutural types have been made. Among them, the 66 small molecule SOAT inhibitor CI-976 exhibit competitive inhibition against fatty acyl-CoA 15 . 67 SOAT is the founding member of the membrane-bound O-acyltransferase (MBOAT) enzyme 68 family, which transfers the acyl chain onto various substrates, including lipids, peptides and 69 small proteins. There are 11 ...

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ACAT1/SOAT1 as a Therapeutic Target for Alzheimer's Disease

Cited by 86 publications

References 137 publications

In vitro exploration of ACAT contributions to lipid droplet formation during adipogenesis

In vitro exploration of ACAT contributions to lipid droplet formation during adipogenesis

Sterol-O acyltransferase 1 is inhibited by gga-miR-181a-5p and gga-miR-429-3p through the TGFβ pathway in endodermal epithelial cells of Japanese quail

Inhibition mechanism of human sterol O-acyltransferase 1 by competitive inhibitor

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